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Objectives To develop and evaluate the performance of the novel SLE-DAS Responder Index (SLE-DAS RI) as an efficacy endpoint in SLE trials and to assess the utility of SLE-DAS in identifying moderate-to-severe disease activity (MSDA).Methods This post-hoc analysis pooled individual patient data from the placebo arms of three anifrolumab trials (MUSE, TULIP-1, TULIP-2). The SLE-DAS RI was defined as a reduction in SLE-DAS>=1.72 from baseline and a score <=7.64 at week 52, capturing both meaningful improvement and resolution of MSDA. Associations between SLE-DAS RI response and changes in physician-reported outcomes (SLEDAI-2K, BILAG-2004, SLE-DAS, PhGA, CLASI-A), glucocorticoid exposure, and health-related quality of life (HR-QoL; SF-36, LupusQoL, EQ-5D, FACIT-F, PtGA) were assessed using regression models. Predictive performance for HR-QoL was compared with BICLA and SRI-4. Flare occurrence was evaluated using the SLE-DAS flare tool. MSDA (SLE-DAS>7.64) was assessed at screening and at week 12 by comparing HR-QoL between MSDA and non-MSDA patients.Results Among 438 patients, 34.0% achieved SLE-DAS RI response at week 52. Responders showed greater improvements in SLE-DAS, SLEDAI-2K, PhGA and CLASI-A (p<0.0001 for all). None exhibited major organ involvement; only 0.6% developed new BILAG A/B domains, and glucocorticoid exposure was lower (2729 vs 3428mg, p=0.001). Responders experienced significantly greater improvements in all HR-QoL instruments ( figure 1). Multiple regression confirmed SLE-DAS RI as the most consistent predictor of HR-QoL, outperforming BICLA and SRI-4. Responders had a 41.9% lower flare risk and higher proportion of flare-free status (40.1% vs 19.7%, p<0.001). At screening, SLE-DAS MSDA identified 96.1% of active patients and better reflected HR-QoL at week 12.Abstract S13:01 Figure 1Conclusions The SLE-DAS RI is a robust efficacy endpoint capturing meaningful improvement and resolution of MSDA while aligning with HR-QoL, reducing glucocorticoid burden, and predicting sustained disease control. Its superior predictive value for HR-QoL supports its use as a next-generation endpoint in SLE trials. SLE-DAS accurately classifies MSDA, supporting use in eligibility assessment.Acknowledgement This publication is based on research using data from data contributors AstraZeneca that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication.